Three-Dimensional Human iPSC-Derived Artificial Skeletal Muscles Model Muscular Dystrophies and Enable Multilineage Tissue Engineering
Sara Martina Maffioletti,
Shilpita Sarcar,
Alexander B.H. Henderson,
Ingra Mannhardt,
Luca Pinton,
Louise Anne Moyle,
Heather Steele-Stallard,
Ornella Cappellari,
Kim E. Wells,
Giulia Ferrari,
Jamie S. Mitchell,
Giulia E. Tyzack,
Vassilios N. Kotiadis,
Moustafa Khedr,
Martina Ragazzi,
Weixin Wang,
Michael R. Duchen,
Rickie Patani,
Peter S. Zammit,
Dominic J. Wells,
Thomas Eschenhagen,
Francesco Saverio Tedesco
Affiliations
Sara Martina Maffioletti
Department of Cell and Developmental Biology, University College London, London WC1E 6DE, UK
Shilpita Sarcar
Department of Cell and Developmental Biology, University College London, London WC1E 6DE, UK
Alexander B.H. Henderson
Department of Cell and Developmental Biology, University College London, London WC1E 6DE, UK
Ingra Mannhardt
Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg Eppendorf (UKE), 20246 Hamburg, Germany; DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Germany
Luca Pinton
Department of Cell and Developmental Biology, University College London, London WC1E 6DE, UK; Randall Centre for Cell and Molecular Biophysics, King’s College London, London SE1 1UL, UK
Louise Anne Moyle
Department of Cell and Developmental Biology, University College London, London WC1E 6DE, UK
Heather Steele-Stallard
Department of Cell and Developmental Biology, University College London, London WC1E 6DE, UK; Randall Centre for Cell and Molecular Biophysics, King’s College London, London SE1 1UL, UK
Ornella Cappellari
Department of Comparative Biomedical Sciences, Royal Veterinary College, London NW1 0TU, UK
Kim E. Wells
Department of Comparative Biomedical Sciences, Royal Veterinary College, London NW1 0TU, UK
Giulia Ferrari
Department of Cell and Developmental Biology, University College London, London WC1E 6DE, UK
Jamie S. Mitchell
Institute of Neurology, University College London, London WC1N 3BG, UK; The Francis Crick Institute, London NW1 1AT, UK
Giulia E. Tyzack
Institute of Neurology, University College London, London WC1N 3BG, UK; The Francis Crick Institute, London NW1 1AT, UK
Vassilios N. Kotiadis
Department of Cell and Developmental Biology, University College London, London WC1E 6DE, UK
Moustafa Khedr
Department of Cell and Developmental Biology, University College London, London WC1E 6DE, UK
Martina Ragazzi
Department of Cell and Developmental Biology, University College London, London WC1E 6DE, UK
Weixin Wang
Department of Cell and Developmental Biology, University College London, London WC1E 6DE, UK
Michael R. Duchen
Department of Cell and Developmental Biology, University College London, London WC1E 6DE, UK
Rickie Patani
Institute of Neurology, University College London, London WC1N 3BG, UK; The Francis Crick Institute, London NW1 1AT, UK
Peter S. Zammit
Randall Centre for Cell and Molecular Biophysics, King’s College London, London SE1 1UL, UK
Dominic J. Wells
Department of Comparative Biomedical Sciences, Royal Veterinary College, London NW1 0TU, UK
Thomas Eschenhagen
Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg Eppendorf (UKE), 20246 Hamburg, Germany; DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Germany
Francesco Saverio Tedesco
Department of Cell and Developmental Biology, University College London, London WC1E 6DE, UK; Corresponding author
Summary: Generating human skeletal muscle models is instrumental for investigating muscle pathology and therapy. Here, we report the generation of three-dimensional (3D) artificial skeletal muscle tissue from human pluripotent stem cells, including induced pluripotent stem cells (iPSCs) from patients with Duchenne, limb-girdle, and congenital muscular dystrophies. 3D skeletal myogenic differentiation of pluripotent cells was induced within hydrogels under tension to provide myofiber alignment. Artificial muscles recapitulated characteristics of human skeletal muscle tissue and could be implanted into immunodeficient mice. Pathological cellular hallmarks of incurable forms of severe muscular dystrophy could be modeled with high fidelity using this 3D platform. Finally, we show generation of fully human iPSC-derived, complex, multilineage muscle models containing key isogenic cellular constituents of skeletal muscle, including vascular endothelial cells, pericytes, and motor neurons. These results lay the foundation for a human skeletal muscle organoid-like platform for disease modeling, regenerative medicine, and therapy development. : Maffioletti et al. generate human 3D artificial skeletal muscles from healthy donors and patient-specific pluripotent stem cells. These human artificial muscles accurately model severe genetic muscle diseases. They can be engineered to include other cell types present in skeletal muscle, such as vascular cells and motor neurons. Keywords: skeletal muscle, pluripotent stem cells, iPS cells, myogenic differentiation, tissue engineering, disease modeling, muscular dystrophy, organoids
